No definitive conclusions can be drawn about the effectiveness of vitamin B12 testing since no prospective comparative trials have been conducted to directly assess the impact of testing on health outcomes in healthy populations or in patients with chronic disease associated with vitamin B12 deficiency.
7.4 Harms associated with vitamin B12 testing
No trials designed to directly measure the risks or harms associated with vitamin B12 testing were identified. However, vitamin B12 testing relies on a blood draw, which is a safe procedure. Vitamin B12 supplements are generally considered safe when taken in amounts that are not higher than the recommended dietary allowance. Thus, it is likely that the consequences of inaccurate or inappropriately interpreted serum vitamin B12 test results, such as a false positive, are relatively small.
7.5 Diagnostic performance of vitamin B12 tests
A 2011 systematic review by Willis and colleagues evaluated the diagnostic accuracy of serum B12 tests using MMA, Hcy and holoTC as a reference standard. The review noted that the available evidence on the diagnostic accuracy of the serum vitamin B12 test is low, due to the lack of a gold reference standard. From the available evidence, diagnosis of conditions amenable to vitamin B12 supplementation on the basis of serum vitamin B12 levels alone cannot be considered a reliable approach to investigating suspected vitamin B12 deficiency. Across clinical indications, practice settings and different methodologies, the authors of the review found low levels of test sensitivity and, to a lesser extent, specificity. The authors of the review also demonstrated that the transition from older assay methods to newer technologies, such as chemiluminescence, was not associated with improved diagnostic accuracy.
Important findings from the 2011 review are summarised below:
-
There is currently no consensus on the best method to estimate vitamin B12 deficiency and vitamin B12 status.
-
Measurement of total serum vitamin B12 is widely used as a standard screening test but there are problems with the sensitivity and specificity of this test.
-
The determination of serum vitamin B12 diagnostic accuracy is difficult to establish due to the absence of a gold standard.
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The accuracy of the serum vitamin B12 assay differs according to existing reference standards (MMA, Hcy, or holoTC) and subgroups; however, not all variation in serum vitamin B12 test performance may be attributed to serum vitamin B12 assay deficiency.
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The absence of a gold standard method hampers the ability to compare the various markers of B12 deficiency (MMA, Hcy, and holoTC) with each other.
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All four biochemical tests have poor specificity.
There is evidence which indicates that holoTC has a comparable or better diagnostic accuracy to that of total serum vitamin B12. This was demonstrated in nine comparative studies that reported a significantly greater area under the curve for holoTC than for vitamin B12 in detecting vitamin B12 deficiency. Only one study reported that the holoTC assay has poorer diagnostic accuracy than the serum vitamin B12 assay. However, there is insufficient evidence to establish holoTC testing as an alternative to either total serum vitamin B12, or levels of MMA or homocysteine in the diagnosis of vitamin B12 deficiency.
7.6 Cost implications of vitamin B12 testing
It is unknown whether measurement of vitamin B12 levels is cost-effective. No costing studies or economic analyses of vitamin B12 testing were identified.
7.7 Conclusions
There has been a substantial increase in the number of claims for vitamin B12/folate testing over the past ten years. Analysis of MBS data indicates that the majority of vitamin B12 testing services are requested by GPs and OMPs for the purposes of screening or testing, rather than follow-up monitoring. There are no Australian clinical practice guidelines that either advocate or recommend against routine testing for vitamin B12. The international clinical practice guidelines vary widely in their recommendations. While some recommend vitamin B12 test as screening tools in commonly encountered illnesses such as dementia, others suggest restricting testing to patients who have already undergone pre-test investigations such as a full blood count or blood film examination. There are no recommendations on the frequency of vitamin B12 testing and there is no direct evidence regarding the clinical utility of vitamin B12 testing in any population.
APPENDIX 1 – References
1. Festen HP. Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol Suppl 1991;188:1-7.
2. Elia M. Oral or parenteral therapy for B12 deficiency. Lancet 1998 Nov 28;352(9142):1721-2.
3. Oh R, Brown DL. Vitamin B12 deficiency. American family physician 2003 Mar 1;67(5):979-86.
4. Wikipedia. Cofactor (biochemistry). 2012; Available from: http://en.wikipedia.org/wiki/Cofactor_(biochemistry).
5. Stabler SP. Screening the older population for cobalamin (vitamin B12) deficiency. J Am Geriatr Soc 1995 Nov;43(11):1290-7.
6. center UoMM. Methylmalonic acid. 2012; Available from: http://www.umm.edu/ency/article/003565.htm.
7. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr 2011 Aug;94(2):666S-72S.
8. Medicine Io, Board FaN. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC1998.
9. National Health and Medical Research Council, Health. NZMo. Nutrient reference values for Australia and New Zealand including recommended dietary intakes. Canberra, ACT2006; Available from: http://www.nhmrc.gov.au/guidelines/publications/n35-n36-n37 (accessed May 2012). .
10. Watanabe F. Vitamin B12 sources and bioavailability. Exp Biol Med (Maywood) 2007 Nov;232(10):1266-74.
11. Gilsing AM, Crowe FL, Lloyd-Wright Z, Sanders TA, Appleby PN, Allen NE, et al. Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians and vegans: results from a cross-sectional analysis of the EPIC-Oxford cohort study. Eur J Clin Nutr 2010 Sep;64(9):933-9.
12. US Department of Agriculture ARS. USDA National Nutrient Database for Standard Reference, Release 24. 2011; Available from: http://www.ars.usda.gov/ba/bhnrc/ndl.
13. Food Standards ANZ. Adding vitamins and minerals to food. 2012; Available from: http://www.foodstandards.gov.au/consumerinformation/fortification.cfm.
14. Zealand FSAN. NUTTAB 2010 online searchable database. 2012; Available from: http://www.foodstandards.gov.au/consumerinformation/nuttab2010/nuttab2010onlinesearchable database/onlineversion.cfm (accessed Nov 2011). .
15. Hathcock JN. Vitamins and minerals: efficacy and safety. Am J Clin Nutr 1997 Aug;66(2):427-37.
16. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999 Jun 28;159(12):1289-98.
17. Mangels R MV, Messina M. The dietitians’ guide to vegetarian diets: issues and applications. 3rd ed. Sudbury M, editor: Jones & Bartlett Learning; 2010.
18. Halsted CH. Folate deficiency in alcoholism. Am J Clin Nutr 1980 Dec;33(12):2736-40.
19. Lindenbaum J. Folate and vitamin B12 deficiencies in alcoholism. Semin Hematol 1980 Apr;17(2):119-29.
20. Nkrumah FK, Nathoo KJ, Sanders DM. Iron, folate and vitamin B12 in severe protein-energy malnutrition. Cent Afr J Med 1988 Mar;34(3):39-43.
21. Higgins JR, Quinlivan EP, McPartlin J, Scott JM, Weir DG, Darling MR. The relationship between increased folate catabolism and the increased requirement for folate in pregnancy. Bjog 2000 Sep;107(9):1149-54.
22. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med 1993 Nov;86(11):703-8.
23. Groenen PM, van Rooij IA, Peer PG, Gooskens RH, Zielhuis GA, Steegers-Theunissen RP. Marginal maternal vitamin B12 status increases the risk of offspring with spina bifida. Am J Obstet Gynecol 2004 Jul;191(1):11-7.
24. Suarez L, Hendricks K, Felkner M, Gunter E. Maternal serum B12 levels and risk for neural tube defects in a Texas-Mexico border population. Ann Epidemiol 2003 Feb;13(2):81-8.
25. Gueant JL, Safi A, Aimone-Gastin I, Rabesona H, Bronowicki JP, Plenat F, et al. Autoantibodies in pernicious anemia type I patients recognize sequence 251-256 in human intrinsic factor. Proc Assoc Am Physicians 1997 Sep;109(5):462-9.
26. Kaushansky K BE, Seligsohn U, Lichtman MA, Kipps TJ, Prchal JT,. Folate, cobalamin, and megaloblastic anemias. 8th ed ed. R. G, editor. New York: McGraw-Hill; 2010.
27. Sipponen P, Laxen F, Huotari K, Harkonen M. Prevalence of low vitamin B12 and high homocysteine in serum in an elderly male population: association with atrophic gastritis and Helicobacter pylori infection. Scand J Gastroenterol 2003 Dec;38(12):1209-16.
28. Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2007 Nov;23(6):595-601.
29. Green R MJ. Handbook of Vitamins. 4th ed. Zempleni J RR, editor. Boca Raton, FL: Taylor & Francis Group; 2007.
30. Aarts EO, Janssen IM, Berends FJ. The gastric sleeve: losing weight as fast as micronutrients? Obes Surg 2011 Feb;21(2):207-11.
31. Ponziani FR, Cazzato IA, Danese S, Fagiuoli S, Gionchetti P, Annicchiarico BE, et al. Folate in gastrointestinal health and disease. Eur Rev Med Pharmacol Sci 2012 Mar;16(3):376-85.
32. Yakut M, Ustun Y, Kabacam G, Soykan I. Serum vitamin B12 and folate status in patients with inflammatory bowel diseases. Eur J Intern Med 2010 Aug;21(4):320-3.
33. Vanderbrink BA, Cain MP, King S, Meldrum K, Kaefer M, Misseri R, et al. Is oral vitamin B(12) therapy effective for vitamin B(12) deficiency in patients with prior ileocystoplasty? J Urol 2010 Oct;184(4 Suppl):1781-5.
34. Kapadia CR. Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport. Gastroenterologist 1995 Dec;3(4):329-44.
35. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Variable hematologic presentation of autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion. Blood 2006 Feb 15;107(4):1673-9.
36. Lahner E, Annibale B. Pernicious anemia: new insights from a gastroenterological point of view. World J Gastroenterol 2009 Nov 7;15(41):5121-8.
37. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. Faseb J 1993 Nov;7(14):1344-53.
38. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988 Jun 30;318(26):1720-8.
39. Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. The American journal of psychiatry 2002 Dec;159(12):2099-101.
40. Ramos MI, Allen LH, Mungas DM, Jagust WJ, Haan MN, Green R, et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2005 Dec;82(6):1346-52.
41. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology 2001 May 8;56(9):1188-94.
42. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997 Jul 24;337(4):230-6.
43. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program 2003:62-81.
44. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. American Journal of Clinical Nutrition 2011;94(2):666S-72S.
45. Herzlich B, Herbert V. Depletion of serum holotranscobalamin II. An early sign of negative vitamin B12 balance. Lab Invest 1988 Mar;58(3):332-7.
46. Herrmann W, Obeid R, Schorr H, Geisel J. Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med 2003 Nov;41(11):1478-88.
47. Morkbak AL, Poulsen SS, Nexo E. Haptocorrin in humans. Clin Chem Lab Med 2007;45(12):1751-9.
48. Carmel R. Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin Chem 2003 Aug;49(8):1367-74.
49. Ulleland M, Eilertsen I, Quadros EV, Rothenberg SP, Fedosov SN, Sundrehagen E, et al. Direct assay for cobalamin bound to transcobalamin (holo-transcobalamin) in serum. Clin Chem 2002 Mar;48(3):526-32.
50. Green R. Metabolite assays in cobalamin and folate deficiency. Bailliere's clinical haematology 1995 Sep;8(3):533-66.
51. Miller JW, Garrod MG, Rockwood AL, Kushnir MM, Allen LH, Haan MN, et al. Measurement of total vitamin B12 and holotranscobalamin, singly and in combination, in screening for metabolic vitamin B12 deficiency. Clin Chem 2006 Feb;52(2):278-85.
52. Hvas AM, Nexo E. Holotranscobalamin--a first choice assay for diagnosing early vitamin B deficiency? J Intern Med 2005 Mar;257(3):289-98.
53. Heil SG, de Jonge R, de Rotte MC, van Wijnen M, Heiner-Fokkema RM, Kobold AC, et al. Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study. Ann Clin Biochem 2012 Mar;49(Pt 2):184-9.
54. Axis-Shield. Active-B12 the next level of vitamin B12 testing. 2012; Available from: http://www.active-b12.com/Assays-Active-B12.
55. Sumner AE, Chin MM, Abrahm JL, Berry GT, Gracely EJ, Allen RH, et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery. Ann Intern Med 1996 Mar 1;124(5):469-76.
56. Frenkel EP, Yardley DA. Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin B12 (cobalamin) in pregnancy and gynecology. Hematology/oncology clinics of North America 2000 Oct;14(5):1079-100, viii.
57. Kara N, Senes M, Coskun O, Inan L, Saydam G, Yucel D. Urinary methylmalonic acid levels in patients with acute ischemic stroke. Clin Biochem 2009 May;42(7-8):578-83.
58. Clarke R, Birks J, Nexo E, Ueland PM, Schneede J, Scott J, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr 2007 Nov;86(5):1384-91.
59. Hooshmand B, Solomon A, Kareholt I, Rusanen M, Hanninen T, Leiviska J, et al. Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 2012 Feb;271(2):204-12.
60. Lildballe DL, Fedosov S, Sherliker P, Hin H, Clarke R, Nexo E. Association of cognitive impairment with combinations of vitamin B(1)(2)-related parameters. Clin Chem 2011 Oct;57(10):1436-43.
61. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. American journal of hematology 1990 Jun;34(2):99-107.
62. Vorvick LaM, J. Vitamin B12 levels-Results. 2010; Available from: http://www.umm.edu/ency/article/003705res.htm.
63. Herbert V. Present knowledge in Nutrition. 7 ed: Institute Press; 1996.
64. Ubbink J. What is a desirable homocysteine level? . In: Carmel R JD, editor. Homocysteine in health and disease. Cambridge, UK: Cambridge University Press; 2001. p. 485-90.
65. Selhub J. Homocysteine metabolism. Annu Rev Nutr 1999;19:217-46.
66. Bradford GS, Taylor CT. Omeprazole and vitamin B12 deficiency. The Annals of pharmacotherapy 1999 May;33(5):641-3.
67. Mirkazemi C, Peterson GM, Tenni PC, Jackson SL. Vitamin B12 deficiency in Australian residential aged care facilities. J Nutr Health Aging 2012 Mar;16(3):277-80.
68. Flood VM, Smith WT, Webb KL, Rochtchina E, Anderson VE, Mitchell P. Prevalence of low serum folate and vitamin B12 in an older Australian population. Aust N Z J Public Health 2006 Feb;30(1):38-41.
69. AGREE Next Steps Consortium. The AGREE II Instrument 2009; Available from: http://www.agreetrust.org
70. Richardson WS, Scott MD WM, et al. The well built clinical question: a key to evidence based decisions. ACP Journal Club 1995;123:ppA-12. .
71. Ontario. HQ. Serum Vitamin B12 Testing: A Rapid Review. . Ontario, Canada. : Health Quality Ontario.2012. .
72. Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE. Vitamin B12 (cobalamin) deficiency in elderly patients. Canadian Medical Association Journal 2004;171(3):251-9.
73. Smellie WSA, Wilson D, McNulty CAM, Galloway MJ, Spickett GA, Finnigan DI. Best practice in primary care pathology: Review 1
J Clin Pathol 2005;58(10):1016-24.
74. Health. BCMo. Cobalamin (vitamin B 12 ) Deficiency - Investigation & Management. British Columbia: BC Ministry of Health2012.
75. group. Aw. Appraisal of guidelines for research and evaluation II (AGREE). 2009; Available from: http://www.agreetrust.org/.
76. BCSH. Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies Clin Lab Haematol 1994;16:101-5.
77. (KDIGO) KDIGO. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease2012.
78. Excellence NIfHaC. Dementia: supporting people with dementia and their carers in health and social care.: NICE2012 Contract No.: 42.
79. Galvin JE, Sadowsky CH. Practical guidelines for the recognition and diagnosis of dementia. J Am Board Fam Med 2012 May-Jun;25(3):367-82.
80. Committee BGaPA. Cognitive impairment in the elderly: recognition, diagnosis and management. British Columbia: BC MInistry of Health2007.
81. Pitner JK, Bachman DL. A synopsis of the practice parameters on dementia from the american academy of neurology on the diagnosis of dementia. Consult Pharm 2004 Jan;19(1):52-63.
82. NICE. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy) in adults and children. London: National Institute for Health and Clinical Excellence2007.
83. England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009 Jan 13;72(2):185-92.
84. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. Aliment Pharmacol Ther 2006 Dec;24(11-12):1507-23.
85. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. The Cochrane database of systematic reviews 2003(3):CD004326.
86. (OHTAC). OHTAC. Appropriateness Phase 1 OHTAC Recommendations: Annual Health Exams, Aspartate Aminotransferase Testing, Chloride Testing, Ferritin Testing, Folate Testing, and Vitamin B12 Testing. . Ontario, Canada. : Health Quality Ontario. ; 2013.
87. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006 Apr 13;354(15):1578-88.
88. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006 Apr 13;354(15):1567-77.
89. Willis CD, Elshaug AG, Milverton JL, Watt AM, Metz MP, Hiller JE, et al. Diagnostic performance of serum cobalamin tests: a systematic review and meta-analysis. Pathology 2011 Aug;43(5):472-81.
90. Matchar DB, McCrory DC, Millington DS, Feussner JR. Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci 1994 Nov;308(5):276-83.
91. Green R. Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies. Food Nutr Bull 2008 Jun;29(2 Suppl):S52-63; discussion S4-6.
92. Willis CD, Elshaug AG, Milverton JL, Watt AM, Metz MP, Hiller JE. Diagnostic performance of serum cobalamin tests: a systematic review and meta-analysis. Pathology 2011 Aug;43(5):472-81.
93. Schrempf W, Eulitz M, Neumeister V, Siegert G, Koch R, Reichmann H, et al. Utility of measuring vitamin B12 and its active fraction, holotranscobalamin, in neurological vitamin B12 deficiency syndromes. J Neurol 2011 Mar;258(3):393-401.
94. Obeid R, Herrmann W. Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid. Clinical Chemistry & Laboratory Medicine 2007;45(12):1746-50.
95. Valente E, Scott JM, Ueland PM, Cunningham C, Casey M, Molloy AM. Diagnostic accuracy of holotranscobalamin, methylmalonic acid, serum cobalamin, and other indicators of tissue vitamin B12 status in the elderly. Clin Chem 2011 Jun;57(6):856-63.
96. Lloyd-Wright Z, Hvas AM, Moller J, Sanders TA, Nexo E. Holotranscobalamin as an indicator of dietary vitamin B12 deficiency. Clin Chem 2003 Dec;49(12):2076-8.
97. Clarke R, Sherliker P, Hin H, Nexo E, Hvas AM, Schneede J, et al. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin. Clin Chem 2007 May;53(5):963-70.
98. Herrmann W, Obeid R. Utility and limitations of biochemical markers of vitamin B12 deficiency. Eur J Clin Invest 2013 Mar;43(3):231-7.
99. Schneede J, Ueland PM. Novel and established markers of cobalamin deficiency: complementary or exclusive diagnostic strategies. Semin Vasc Med 2005 May;5(2):140-55.
100. Baker H, Leevy CB, DeAngelis B, Frank O, Baker ER. Cobalamin (vitamin B12) and holotranscobalamin changes in plasma and liver tissue in alcoholics with liver disease. Journal of the American College of Nutrition 1998 Jun;17(3):235-8.
101. Sculpher M, Manca A, Abbott J, Fountain J, Mason S, Garry R. Cost effectiveness analysis of laparoscopic hysterectomy compared with standard hysterectomy: results from a randomised trial. BMJ 2004 Jan 17;328(7432):134.
102. NHMRC. NHMRC levels of evidence and grades for recommendations for developers of guidelines. [Internet]. Canberra, ACT: National Health and Medical Research Council; 2009. Available from: http://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/evidence_statement_form.pdf.
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